Cancer is a disease whose causes are to be seen, inter alia, in disturbed signal transduction. In particular, deregulated signal transduction via kinases plays a central role in the development, growth and spread of cancer (Blume-Jensen, P. and T. Hunter, Nature 411: 355-365, 2001; Hanahan D. and R. A. Weinberg, Cell 100.57-70, 2000). Various receptor kinases and cytoplasmatic kinases and the growth factors binding to them may thus be involved in deregulated apoptosis, tissue invasion, metastasis and generally in signal transduction mechanisms which lead to cancer.
As already mentioned, one of the principal mechanisms by which cellular regulation is effected is the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are highly regulated and frequently influence one another, as is evident from the existence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs at serine, threonine or tyrosine residues, and protein kinases have therefore been classified in accordance with their specificity of the phosphorylation site in serine/threonine kinases and tyrosine kinases. Since phosphorylation is a very widespread process within cells and since cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a large number of conditions and/or diseases are attributable to either aberrant activation or functional mutations in the molecular components of kinase cascades. Consequently, considerable attention has been devoted to the characterisation of these proteins and compounds that are able to modulate their activity (see review article: Weinstein-Oppenheimer et al., Pharma. &. Therap. 88:229-279, 2000). Various possibilities for the inhibition, regulation and modulation of kinases encompass, for example, the provision of antibodies, antisense ribozymes and inhibitors. In oncology research, tyrosine kinases, in particular, have hitherto been regarded as highly promising targets. Thus, numerous synthetic small molecules are undergoing clinical development as tyrosine kinase inhibitors for the treatment of cancer, for example Iressa® or Gleevec®. However, numerous problems, such as side effects, dosage, resistance of the tumour, tumour specificity and patient selection, still have to be solved here.
Serine/threonine kinases are a class of enzymes which catalyse the transfer of the terminal phosphate of adenosine triphosphate to serine or threonine residues in protein substrates. It is thought that serine/threonine kinases, through substrate phosphorylation, play a crucial rote in signal transduction for a number of cellular functions. Although the precise mechanisms of signal transduction are still unclear, it has been shown that serine/threonine kinases, besides tyrosine kinases, are important factors in cell proliferation, carcinogenesis and cell differentiation.
They may therefore be involved in diseases such as cancer, psoriasis and hyperimmune reactions.
The present invention now relates to compounds of the formula I, preferably as regulators, modulators or inhibitors of protein kinases, in particular of the serine/threonine kinase type, which include, inter alia, phosphoinositide-dependent kinase (PDK). The compounds according to the invention are particularly effective in the inhibition of serine/threonine kinase PDK1.
PDK1 phosphorylates and activates a sub-group of the AGC protein kinase family, comprising PKB, SGK, S6K and PKC isoforms. These kinases are involved in the PI3K signal transduction pathway and control basic cellular functions, such as survival, growth and differentiation. PDK1 is thus an important regulator of diverse metabolic, proliferative and life-sustaining effects.
Diseases caused by protein kinases, such as PDK1, are characterised by anomalous activity or hyperactivity of such protein kinases. Anomalous activity relates either to: (1) the expression in cells which do not usually express these protein kinases; (2) increased kinase expression which results in undesired cell proliferation, such as cancer; (3) increased kinase activity which results in undesired cell proliferation, such as cancer, and/or in hyperactivity of the corresponding protein kinases. Hyperactivity relates either to amplification of the gene which encodes a certain protein kinase or the generation of an activity level which can be correlated with a cell proliferation disease (i.e. the severity of one or more symptoms of the cell proliferation disease increases with increasing kinase level) the bioavailability of a protein kinase can also be influenced by the presence or absence of a set of binding proteins of this kinase.
In the case of PDK1, anomalous activity of the substrates PKB and S6K of this kinase has been observed in a large number of types of cancer which exhibit point mutation of the PTEN gene, which results in uncontrolled proliferation and an increased survival rate. Inhibitors of PDK1 should therefore prove advantageous in the treatment of cancer cells with constitutively activated AGC kinases.
Inhibitors of PDK1 are disclosed, for example, in WO 04/048343 or WO 05/054238.
The most important types of cancer which can be treated using a compound according to the invention include colorectal cancer, small-cell lung cancer, non-small-cell lung cancer, multiple myeloma as well as renal cell carcinoma and endometrium carcinoma, particularly also types of cancer in which PTEN is mutated, inter alia breast cancer, prostate cancer and glioblastoma.
In additions the compounds according to the invention can be used to achieve additive or synergistic effects in certain existing cancer chemotherapies and radiotherapies and/or to restore the efficacy of certain existing cancer chemotherapies and radiotherapies.
A series of diazepinones have been described as kinase inhibitors in WO 04/076424.
The invention was now based on the object of finding further diazepinones having advantageous therapeutic properties which can be used for the preparation of medicaments.